Results of the earliest studies on isolated hearts indicated that optimal concentrations of Na+ , K+ , and Ca++ in extracellular fluid are necessary for contraction of cardiac muscle. Without Na+ , the heart is not excitable and does not beat. As already described, the resting membrane potential is independent of the extracellular [Na+] gradient across the membrane but very much dependent on extracellular [K+]. Decreases or increases in extracellular [K+], especially if they are large or occur quickly, can lead to arrhythmias, loss of excitability of the myocardial cells, and even cardiac arrest. Ca++ is also essential for cardiac contraction. Removal of Ca++ from the extracellular fluid results in decreased contractile force and eventual arrest in diastole. Conversely, an increase in extracellular [Ca++] enhances contractile force, and very high extracellular [Ca++] induces cardiac arrest in systole (rigor). The free intracellular [Ca++] is the factor principally responsible for the contractile state of the myocardium.
The process by which the action potential of the cardiac myocyte leads to contraction is termed excitation-contraction coupling (see also
Chapter 13). Cardiac muscle is excited when a wave of excitation spreads rapidly along the myocardial sarcolemma from cell to cell via gap junctions. Excitation also spreads into the interior of the cells via the T tubules, which invaginate the cardiac fibers at the Z lines. Electrical stimulation at the Z line or the application of Ca++ to the Z lines in a skinned cardiac fiber (whose sarcolemma is removed) elicits localized contraction of the adjacent myofibrils. During the plateau (phase 2) of the action potential, permeability of the sarcolemma by Ca++ increases. Ca++ flows down its electrochemical gradient and enters the cell through calcium channels in the sarcolemma and in the T tubules.
During the action potential, Ca++ enters the cell via calcium channels (L-type). However, the amount of Ca++ that enters the cell interior from the extracellular/ interstitial fluid is not sufficient to induce contraction of the myofibrils. Instead, it acts as a trigger (trigger Ca++) to release Ca++ from the sarcoplasmic reticulum, where the intracellular Ca++ is stored (see
Fig. 13.2 ). Ca++ leaves the sarcoplasmic reticulum through Ca++ release channels, which are called ryanodine receptors because the channel protein binds ryanodine avidly. Cytoplasmic [Ca++] increases from a resting level of approximately 10−7 mol to levels of approximately 10−5 mol during excitation. This Ca++ then binds to the protein troponin C. The Ca++–troponin C complex interacts with tropomyosin to unblock active sites between the actin and myosin filaments. This unblocking initiates cross-bridge cycling and hence contraction of the myofibrils.
Mechanisms that raise cytosolic [Ca++] increase the force developed, and those that lower cytosolic [Ca++] decrease the force developed. For example, catecholamines increase the movement of Ca++ into the cell by phosphorylation of the sarcolemmal calcium channels via a cAMP-dependent protein kinase (see
Fig. 13.4). This in turn causes the release of more Ca++ from the sarcoplasmic reticulum, and as a result, contractile force increases. Increasing extracellular [Ca++] increases the amount of Ca++ that enters the cell via the calcium channels and thereby increases contractile force as just described. Reducing the Na+ gradient across the sarcolemma also increases contractile force, an effect mediated by the 3Na+-Ca++ antiporter that normally extrudes Ca++ from the cell (see